Oncogenic IDH mutations increase heterochromatin-related replication stress without impacting homologous recombination Journal Article

   

Authors:	Schvartzman, J. M.; Forsyth, G.; Walch, H.; Chatila, W.; Taglialatela, A.; Lee, B. J.; Zhu, X.; Gershik, S.; Cimino, F. V.; Santella, A.; Menghrajani, K.; Ciccia, A.; Koche, R.; Sánchez-Vega, F.; Zha, S.; Thompson, C. B.
Article Title:	Oncogenic IDH mutations increase heterochromatin-related replication stress without impacting homologous recombination
Abstract:	Oncogenic mutations in isocitrate dehydrogenases 1 and 2 (IDH1/2) produce 2-hydroxyglutarate (2HG), which inhibits dioxygenases that modulate chromatin dynamics. The effects of 2HG have been reported to sensitize IDH tumors to poly-(ADP-ribose) polymerase (PARP) inhibitors. However, unlike PARP-inhibitor-sensitive BRCA1/2 tumors, which exhibit impaired homologous recombination, IDH-mutant tumors have a silent mutational profile and lack signatures associated with impaired homologous recombination. Instead, 2HG-producing IDH mutations lead to a heterochromatin-dependent slowing of DNA replication accompanied by increased replication stress and DNA double-strand breaks. This replicative stress manifests as replication fork slowing, but the breaks are repaired without a significant increase in mutation burden. Faithful resolution of replicative stress in IDH-mutant cells is dependent on poly-(ADP-ribosylation). Treatment with PARP inhibitors increases DNA replication but results in incomplete DNA repair. These findings demonstrate a role for PARP in the replication of heterochromatin and further validate PARP as a therapeutic target in IDH-mutant tumors. © 2023 Elsevier Inc.
Keywords:	genetics; mutation; neoplasm; neoplasms; homologous recombination; brca1 protein; brca2 protein; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; brca1 protein, human; heterochromatin; isocitrate dehydrogenase; parp; replication stress; oncometabolite; dioxygenase; brca2 protein, human; humans; human; poly(adp-ribose) polymerase inhibitors
Journal Title:	Molecular Cell
Volume:	83
Issue:	13
ISSN:	1097-2765
Publisher:	Cell Press
Date Published:	2023-07-06
Start Page:	2347
End Page:	2356.e8
Language:	English
DOI:	10.1016/j.molcel.2023.05.026
PUBMED:	37311462
PROVIDER:	scopus
PMCID:	PMC10845120
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85164252302&doi=10.1016%2fj.molcel.2023.05.026&partnerID=40&md5=3d546d89b2cd1413407602e923811f4c
Notes:	Article -- Source: Scopus

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